PI3Kγ stimulates a high molecular weight form of myosin light chain kinase to promote myeloid cell adhesion and tumor inflammation

Michael C. Schmid (), Sang Won Kang, Hui Chen, Marc Paradise, Anghesom Ghebremedhin, Megan M. Kaneda, Shao-Ming Chin, Anh Do, D. Martin Watterson and Judith A. Varner ()
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Michael C. Schmid: University of California, San Diego
Sang Won Kang: Ewha Womans University
Hui Chen: University of California, San Diego
Marc Paradise: University of California, San Diego
Anghesom Ghebremedhin: University of California, San Diego
Megan M. Kaneda: University of California, San Diego
Shao-Ming Chin: University of California, San Diego
Anh Do: University of California, San Diego
D. Martin Watterson: Northwestern University
Judith A. Varner: University of California, San Diego

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Myeloid cells play key roles in cancer immune suppression and tumor progression. In response to tumor derived factors, circulating monocytes and granulocytes extravasate into the tumor parenchyma where they stimulate angiogenesis, immune suppression and tumor progression. Chemokines, cytokines and interleukins stimulate PI3Kγ-mediated Rap1 activation, leading to conformational changes in integrin α4β1 that promote myeloid cell extravasation and tumor inflammation Here we show that PI3Kγ activates a high molecular weight form of myosin light chain kinase, MLCK210, that promotes myosin-dependent Rap1 GTP loading, leading to integrin α4β1 activation. Genetic or pharmacological inhibition of MLCK210 suppresses integrin α4β1 activation, as well as tumor inflammation and progression. These results demonstrate a critical role for myeloid cell MLCK210 in tumor inflammation and serve as basis for the development of alternative approaches to develop immune oncology therapeutics.

Date: 2022
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DOI: 10.1038/s41467-022-29471-6

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